Normal cardiac rhythm and cardiac arrhythmias have unique characteristics in relation to age. Although these characteristics in part appear to result from age-related changes in cellular electrophysiologic properties, they also appear to bear a strong relationship to developmental changes in the autonomic nervous system. The purpose of this proposal is to determine how developmental changes in alpha and beta adrenergic as well as cholinergic function modify rhythm and may predispose to arrhythmias. Cellular and in situ electrophysiologic techniques will be used to study responses to cholinergic and alpha and beta adrenergic agonists and antagonists of sinus node, atrioventricular node and atrial and ventricular specialized conducting fibers from neonatal, young, adult and old dogs and rabbits. By determining how the agonists and antagonists modify automaticity, conduction and refractoriness as well as action potential characteristics, for animals of different ages we will determine how the response to autonomic mediators changes with age. To determine the relevance of our cellular findings to the in situ heart, studies of agonists and antagonists on sinus node and ventricular automaticity will be done in chronically instrumented young, adult and old dogs with heart block. To determine the relationship of sympathetic nerve growth to physiologic responsiveness to adrenergic agents we shall use nerve growth factor and its antibody to modify the sympathetic growth in neonatal mice. Effects on sino-atrial function and response to adrenergic agonists and antagonists again will be studied with microelectrode techniques. As a reslt of those studies we will learn how autonomic mediators modify automaticity, conduction and refractoriness in cardiac fibers from animals of different ages. We shall be able to determine the extent to which age-related changes in the response to mediators of the sympathetic and parasympathetic nervous systems modify cardiac rate and rhythm.